An important pathologic feature of AD is the formation of extracellular senile plaques in the brain, whose major component is a small peptide called ?-amyloid (A?). Multiple lines of evidence suggest that A? is the prime culprit for AD pathogenesis: overproduction/accumulation of A? in the brain triggers a cascade of neurodegenerative steps resulting in the formation of neuritic plaques and intra-neuronal fibrillary tangles and neuronal loss. Therefore, proteins/enzymes involved in A? generation that reduce the level of A? could potentially be used therapeutically for disease intervention. A? peptides are derived from ?-amyloid precursor protein (APP) through sequential cleavages by ?-secretase and ?-secretase. BACE1 is the major ?-secretase and inhibition of BACE1 activity has become a hot target for development of new AD drugs. In the preliminary studies, we have identified one BACE1-interacting protein, cutA divalent cation tolerance homolog of E.coli (CutA). Importantly, we found that CutA can affect cell surface accumulation of BACE1, ?-cleavage of APP, and A? levels. Moreover, we found that the level of CutA is decreased in the brains of AD patients. Previous studies suggest that CutA may regulate the level/activity of acetylcholinesterase (AChE), an enzyme that degrades acetylcholine and an important target of inhibition for current AD treatments. In addition, CutA may be involved in the homeostasis of copper, a heavy metal linked to AD. We also found that copper can affect secretion of CutA, as well as A? levels. Therefore, we hypothesize that CutA plays an important role in AD through its interaction with BACE1, through its effect on AChE, and through its participation in copper-mediated AD pathologies and/or regulation of copper homeostasis. In this proposal we will carry out detailed studies to ascertain the effects of CutA on BACE1- and copper-mediated APP processing/A? generation, on AChE activity and on copper homeostasis. Furthermore, we will investigate the level of CutA in the brains of AD patients and transgenic mice to establish a direct link between CutA and AD. Moreover, we will use an adeno-associated virus system to deliver CutA into the brains of APP/PS1/tau triple transgenic AD mice and study whether overexpression of CutA can reduce A? plaques and tau tangles, as well as improve synaptic functions in AD mice. Together, our results will elucidate the involvement of CutA in AD and the underlying mechanism, identifying a new potential therapeutic target for disease intervention. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is one of the most important areas in medical research today and so far there is no cure or meaningfully effective treatment for this devastating neurodegenerative disorder. Demonstration of CutA as an important player in AD will have a significant impact on basic research and developing new strategies for treating AD.